Silencing the OCT4-PG1 pseudogene reduces OCT-4 protein levels and changes characteristics of the multidrug resistance phenotype in chronic myeloid leukemia

• Published in: Molecular biology reports Vol. 46; no. 2; pp. 1873 - 1884
• Main Authors: Lettnin, Aline Portantiolo, Wagner, Eduardo Felipe, Carrett-Dias, Michele, dos Santos Machado, Karina, Werhli, Adriano, Cañedo, Andrés Delgado, Trindade, Gilma Santos, de Souza Votto, Ana Paula
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.04.2019; Springer Nature B.V
• Subjects: ABC transporters; Animal Anatomy; Animal Biochemistry; Arachidonate 5-Lipoxygenase - metabolism; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Transporters - genetics; Biomedical and Life Sciences; Cancer; Cell Line, Tumor; Chemotherapy; Chronic myeloid leukemia; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Embryonic Stem Cells - metabolism; Epigenetics; Gene Expression; Gene regulation; Gene Silencing - physiology; Genotype & phenotype; Histology; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Life Sciences; Morphology; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Multidrug resistant organisms; Myeloid leukemia; Neoplastic Stem Cells - metabolism; Oct-4 gene; Oct-4 protein; Octamer Transcription Factor-3 - genetics; Original Article; Phenotype; Phenotypes; Protein structure; Proteins; Pseudogenes; SOXB1 Transcription Factors - metabolism; Stem cells; Transcription factors; P-glycoprotein; ABC transporters; Cancer stem cells; MRP1 protein; STRING database
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-019-04639-4

Cancer stem cells show epigenetic plasticity and intrinsic resistance to anti-cancer therapy, rendering capable of initiating cancer relapse and progression. Transcription factor OCT-4 regulates various pathways in stem cells, but its expression can be regulated by pseudogenes. This work evaluated how OCT4-PG1 pseudogene can affect OCT-4 expression and mechanisms related to the multidrug resistance (MDR) phenotype in FEPS cells. Considering that OCT-4 protein is a transcription factor that regulates expression of ABC transporters, level of gene expression, activity of ABC proteins and cell sensitivity to chemotherapy were evaluated after OCT4-PG1 silencing. Besides we set up a STRING network. Results showed that after OCT4-PG1 silencing, cells expressed OCT-4 gene and protein to a lesser extent than mock cells. The gene and protein expression of ABCB1 , as well as its activity were reduced. On the other hand, ALOX5 and ABCC1 genes was increased even as the activity of this transporter. Moreover, the silencing cells become sensitive to two chemotherapics tested. The network structure demonstrated that OCT4-PG1 protein interacts directly with OCT-4, SOX2, and NANOG and indirectly with ABC transporters. We conclude that OCT4-PG1 pseudogene plays a key role in the regulation OCT-4 transcription factor, which alters MDR phenotype in the FEPS cell line.